I had the opportunity to participate in the American Thoracic Society 2015 meeting over the past few days as part of two sessions: a day-long course on the connection between anesthesia and sleep (especially obstructive sleep apnea) and a symposium on personalized medicine for sleep apnea. My talks focused on the personalized medicine approach to the selection of surgical procedures to treat sleep apnea, including drug-induced sleep endoscopy. I will share some brief highlights from other talks at these sessions, as I have discussed many of these themes in other blog posts and elsewhere on my website. An important note is that this post is not meant to provide an exhaustive list of meeting highlights because there is so much outstanding science on a wide range of disorders and diseases.
Sleep apnea phenotypes: different people with sleep apnea are different
Multiple factors contribute to sleep apnea, including abnormal anatomy (the target of surgery and the most important factor), reflex muscle activation in the throat, control of breathing, and low arousal threshold. Different factors are more important in some people than others, and it is important that up to 70% of patients have at least some influence of a factor other than anatomy. Much of this innovative research on sleep apnea phenotyping (identifying the relative importance of these various factors in an individual patient) has been performed by the Brigham and Women’s Hospital Sleep and Breathing Research Group. This team has been led by premiere scientists (David P. White, MD, Atul Malhotra, MD (now at the University of California, San Diego), and Andrew Wellman, MD, PhD) and has spawned a number of excellent research laboratories around the world, including that of Danny Eckert, PhD of the University of New South Wales and Neuroscience Research Australia. Several researchers from these groups in the US and Australia discussed their work to identify the relative influence of these different components for individual patients. In short, patients with favorable anatomy (defined by a pharyngeal critical closing pressure, or Pcrit, of at least -5 cm of water pressure) do not have sleep apnea, whereas those with unfavorable anatomy (Pcrit greater than +5 cm of water pressure) always have severe obstructive sleep apnea. The other factors that play a role in sleep apnea are particularly important for those with borderline anatomy (Pcrit between -2 and -5 cm of water pressure). They presented techniques–some simple, some complex–for determining these relative influences, but more importantly they proposed some strategies to make the determinations that are complex potentially much more straightforward. It has been an honor to collaborate with the team at Brigham and Women’s Hospital on some of my own research over the years, and it is humbling to know that you are always the dumbest person in the room whenever I am speaking with them.
Control of muscles surrounding the upper airway
Richard Horner, PhD, a member of the Department of Physiology at the University of Toronto spoke about the control of muscle tone during sleep. We know that muscle tone decreases in sleep, with greater decreases in REM than non-REM sleep. This change in muscle tone has been most closely studied in the genioglossus muscle, the major tongue muscle, as it is important in sleep apnea and physically large enough to study relatively easily. Acetylcholine is a chemical important in nerve function throughout our body, including in our brain. Acetylcholine activity decreases muscle tone in the key areas of the brain (hypoglossal motor nucleus) that control genioglossus muscle tone, such that blocking this activity with medications increases muscle tone. The issue is that blocking activity through various chemical pathways can have a wide range of unintended consequences; for example, blocking one type of acetylcholine channel can cause seizures. Their laboratory and other researchers are working on focused treatment, such as a specific receptor called the Kir2.4 potassium channel that is only found in the hypoglossal motor nucleus and a couple of other related areas. Medications to treat obstructive sleep apnea have not proven very beneficial for the large majority of patients to this point, but the search continues.
Sleep apnea and the risk of complications after surgery
Babak Mokhlesi, MD from the Pritzker School of Medicine of the University of Chicago discussed changes that occur after surgery. In short, there is an increased risk of developing or worsening sleep apnea after receiving anesthesia, especially general anesthesia (being completely asleep, with a breathing tube). One in 4 of patients who do not have sleep apnea before surgery develop at least moderate sleep apnea (apnea-hypopnea index of at least 15 events per hour) after surgery; those who have sleep apnea, on average, have worsening in the first few days after surgery. There is a wide variation in the changes in both groups, and the worsening appears to be much more-pronounced in patients older than 40 years of age. The studies show that the changes are not solely related to the fact that patients often sleep on their back after surgery, without as much ability to sleep on their side.
He then showed a number of studies showing that obstructive sleep apnea has been associated with an increased risk of serious complications after surgery. The overwhelming evidence was that the risks of serious complications are still relatively low (approximately 1%), often related to breathing issues, and mostly (often 80%) occurring in the first day after surgery, with an additional 5-10% on the second day after surgery. The takeaways from his talk were that patients undergoing surgery have wide variation in changes, with many having significant sleep apnea after surgery, and the risks of serious complication are low and can be minimized by monitoring patients carefully until they are stable, whether just in the recovery room or admitting patients for 1-2 days.
Frances Chung, MBBS from the University of Toronto Faculty of Medicine led the development of the STOP-BANG questionnaire, a common and simple tool to identify patients with obstructive sleep apnea that is often used in screening patients at a preoperative visit to identify patients who might benefit from testing and possible treatment prior to their planned surgery. I have had the chance to work with Frances and many others who were on the faculty for this course in development of clinical guidelines for preoperative evaluation from the Society of Anesthesia and Sleep Medicine. She showed a number of studies involving the STOP-BANG, stressing that it can be used in multiple ways. With a low score (0-2), it is likely (70-80% chance) that a patient has no or mild sleep apnea, and with a high score (5-8), the chances are much higher (70-80%) of having moderate or severe sleep apnea. In the middle range (3-4), other factors should go into the evaluation if a clinician is considering getting testing like a sleep study before surgery; these factors include age and body mass index (a ratio of weight to height) of at least 35.
She then showed data that at least 1 in 4 patients who are on CPAP at home do not actually receive or use it while in the hospital after surgery, which seems to be an area where health care teams can definitely do better. She also raised the issue of the value of that testing and treatment vs. the delay of surgery. Studies show that patients who get expedited testing and initiation of treatments like CPAP from these preoperative screening programs do not do as well as the typical patient undergoing testing and treatment for sleep apnea, as they are less likely to use CPAP. It is unclear what the right answer is, as there is some reluctance of surgeons and anesthesiologists to delay surgery for patients who need treatment if their patients are not actually going to benefit; for example, we may know that they have sleep apnea but not have effective treatment if they do not use CPAP.
Monitoring patients after surgery and treatment with CPAP
Peter Gay, MD from the Mayo Clinic spoke about the optimal monitoring approaches to identify patients at risk of complication after surgery. Echoing Dr. Chung’s talk (and using data from a study she led), he showed that older patients, those with a greater dose of narcotics to control pain, and those with sleep apnea prior to surgery are those most likely to have notable worsening of sleep apnea after surgery. For postoperative monitoring, there is a wide range of options, including some new technologies and medications, but it is not clear what the best test might be. In fact, he argued that widespread, aggressive monitoring can increase costs dramatically and also worsen patient outcomes. Right now, he advocated for the “eyeball test”, meaning that experienced clinicians need to trust the basic monitoring tools and clinical judgment to make decisions about medications and stability for discharge. It may be helpful for hospitals to have a protocol for identification and management of high-risk patients, but there is no clear best approach.
Nicholas Hill, MD from Tufts University School of Medicine spoke about the use of positive airway pressure (such as CPAP) before and after surgery. I really respect his explanation that positive airway pressure therapy use has become dogma without much evidence in support of such use. There are isolated small studies that show benefit and that it makes sense (certainly to treat patients who are using CPAP before surgery with it after surgery), but every patient may not need CPAP after surgery, even if they have sleep apnea. There may be greater support for use of positive airway pressure (including something called noninvasive ventilation) in patients with a condition called obesity-hypoventilation syndrome or in those with major abdominal surgery that can affect the lungs because these patients typically do not take the deep breaths that keep the lungs functioning properly. Certainly, larger studies need to assess the impact of CPAP treatment in this population.
Sedation and natural sleep
Mervyn Maze, MB ChB, an anesthesiologist and former colleague when I was at the University of California, San Francisco, spoke about the relationship between sedation and natural sleep. The Synaptic Homeostasis model of sleep suggests that slow wave sleep allows synaptic downscaling, the consolidation of primary/important synaptic connections between nerves in the brain and discarding of unimportant synaptic connections. Brain-derived neurotrophic factor (BDNF) accumulates in the brain during wakefulness and promotes slow wave sleep as well as this synaptic downscaling, thought to be a mechanism to allow space for new memories. Mervyn developed a drug called dexmedetomidine that activates alpha-2-adrenoceptors and is used commonly in anesthesia. He then showed multiple studies showing that dexmedetomidine produces some of the same changes that are seen in natural sleep, including brain wave (electroencephalogram) pattern and immune system improvements in humans and increased levels of BDNF in the brains of animals. Importantly, the opposite effects were seen with benzodiazepines, adding to the idea that benzodiazepines are not good sleep aids. Of note, dexmedetomidine is primarily available only in an intravenous form, and it is not safe to use at home because its tendency to decrease heart rate requires that it be used with careful monitoring.